Epilepsy affects 0.5 to 1% of the world's population, and is not controlled by medications in 30-40%. Despite increasing knowledge of molecular and cellular processes in animal models of epilepsy, the genesis and maintenance of epilepsy in humans remains poorly understood. For these reasons, new models for understanding human epilepsy and innovative approaches to the diagnosis and treatment of patients with medically-refractory epilepsy are needed. The broad objective of this project is to use complementary multimodal neuroimaging techniques to identify neurobiological mechanisms underlying epilepsy and epileptogenesis in humans. Building upon evidence that neuroinflammation in animal models of epilepsy may be both cause and consequence of seizures, this project will assess neuroinflammation in patients with temporal lobe epilepsy using a Positron Emission Tomography (PET) marker of activated microglia. It is hypothesized that focal regions of abnormal inflammation will be detected when PET scanning is performed shortly after seizures, and that 1) these regions of inflammation will correspond to the location of a patient's clinically-defined seizure onset zone; 2) degree of inflammation will correlate with measures of disease severity; and 3) regions of inflammation will demonstrate abnormal network-connectivity with other brain areas, as assessed through functional MRI. By providing a neuroimaging marker of localized inflammation in epilepsy, results from this research could aid identification of a patient's epileptogenic zone in the context of clinical evaluations for epilepsy surgery, and could eventually provide a method for monitoring epileptogenesis in patients at risk of developing epilepsy. Building upon the candidate's research background in functional neuroimaging and clinical training in epilepsy, an educational program has been designed to provide her with: 1) education in the conduct of clinical research and applied biostatistics; 2) training in radioligand PET methodology; and 3) a solid understanding of biological mechanisms of epilepsy-related neuroinflammation. A distinguished team of mentors/advisors has been assembled to guide the candidate as she undertakes this multidisciplinary, translationally-based project. This research will improve public health through better understanding and treatment of human epilepsy.